Fibroblast activation protein (FAP) is a membrane-anchored protein that is unique in its selective expression by tumor stromal fibroblasts in epithelial carcinomas, but not by epithelial carcinoma cells, normal fibroblasts, or other normal tissues. The specificity of FAP expression for the tumor stroma, as well as the recent clinical development of inhibitors of FAP enzymatic activity, provides a unique opportunity to investigate and manipulate stromal contributions to tumor growth and invasion. The long-range goal of this research program is to therapeutically target tumor stromal fibroblasts by disrupting their supportive influences on tumor growth, invasion, and metastasis. The objective of this proposal is to determine the biologic effects resulting from perturbations of FAP enzymatic activity by Val-boroPro, the first and only inhibitor of FAP undergoing evaluation in clinical trials. The central hypothesis to be tested is that inhibition of FAP using Val-boroPro will attenuate the growth of pancreas cancer in humans. This hypothesis is formulated based on our observations that 1) the vast majority of pancreas cancers induce stromal fibroblast expression of FAP, 2) FAP overexpression in an animal model potentiates tumor growth, and 3) tumor growth is attenuated by abrogation of FAP enzymatic activity. The rationale for the proposed research is that Val-boroPro appears to have anti-tumor activity as demonstrated by radiographic responses in recent clinical trials. We thus aim to determine the clinical impact of FAP enzymatic inhibition in patients with locally advanced pancreas cancers treated with Val-boroPro. A phase II study will test the central hypothesis that administration of the FAP inhibitor Val-boroPro will demonstrate anti-tumor activity in patients with pancreas cancer, exploiting the synergistic effects of Val-boroPro and gemcitabine to treat patients with locally advanced pancreas cancer. The primary endpoint of this clinical trial will be progression-free survival. In addition we aim to determine changes in FAP enzymatic activity at tumor site with Val-boroPro treatment by conducting a separate clinical trial studying the effects of Val-boroPro treatment on pancreas cancer specimens in a window study of patients scheduled to undergo pancreaticoduodenectomy. Patients with localized pancreas cancer will receive 5 days of Val-boroPro prior to surgical resection, thus enabling direct sampling of treated tumors to determine the degree of inhibition of FAP enzymatic activity, and any downstream effects of FAP at the tumor site. If clinical benefit is seen in patients with pancreas cancer with associated FAP enzymatic inhibition at the tumor site, the relevance to public heath is that this will be considered sufficiently significant to establish the clinical paradigm of stromal inhibition as a novel clinical strategy to treat pancreatic cancer. PUBLIC HEALTH STATEMENT If clinical benefit is seen in patients with pancreas cancer with associated FAP enzymatic inhibition at the tumor site, the relevance to public heath is that this will be considered sufficiently significant to establish the clinical paradigm of stromal inhibition as a novel clinical strategy to treat pancreatic cancer. [unreadable] [unreadable] [unreadable]